Over-expression of PKGI alpha inhibits hypoxia-induced proliferation, Akt activation, and phenotype modulation of human PASMCs: The role of phenotype modulation of PASMCs in pulmonary vascular remodeling

[摘要]：The proliferation of pulmonary artery smooth muscle cells (PASMCs) plays a role in pulmonary vascular remodeling (PVR). Recently, it was shown that vascular smooth muscular cell phenotype modulation is important for their proliferation in other diseases. However, little is known about the role of human PASMC phenotype modulation in the proliferation induced by hypoxia and its molecular mechanism during PVR. In this study, we found using primary cultured human PASMCs that hypoxia suppressed the expression of endogenous PKGI alpha, which was reversed by transfection with a recombinant adenovirus containing the full-length cDNA of PKGI alpha (Ad-PKGI alpha). Ad-PKGI alpha transfection significantly attenuated the hypoxia-induced downregulation of the expression of smooth muscle a-actin (SM-alpha-actin), myosin heavy chain (MHC) and calponin in PASMCs, indicating that hypoxia-induced phenotype modulation was blocked. Furthermore, flow cytometry and H-3-TdR incorporation demonstrated that hypoxia-induced PASMC proliferation was suppressed by upregulation of PKGI alpha. These results suggest that enhanced PKGI alpha expression inhibited hypoxia-induced PASMC phenotype modulation and that it could reverse the proliferation of PASMCs significantly. Moreover, our previous work has demonstrated that Akt protein is activated in the process of hypoxia-induced proliferation of human PASMCs. Interestingly, we found that Akt was not activated by hypoxia when PASMC phenotype modulation was blocked by Ad-PKGI alpha. This result suggests that blocking phenotype modulation might be a key up-stream regulatory target. (C) 2011 Elsevier B.V. All rights reserved.

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